This is an amended proposal from a new investigator now seeking four years of support to examine the relationship between metabolism of iAs and toxicity in cells from liver, skin, urinary bladder and lung. Effects of iAs and trivalent and pentavalent methylated arsenicals on cell viability and proliferation, cellular redox status, induction of oxidative stress, and expression or activation of p53, AP-1 and NF-kB will be examined. The role of antioxidants and antioxidant enzymes in prevention of arsenic-induced effects will be determined. Metabolic conversions of arsenicals will be studied in cultured cells by examining uptake, production of methylated metabolites, interaction of arsenic metabolites with cellular proteins, and efflux of arsenic metabolites from cells. Arsenic metabolites directly responsible for the induction of adverse effects will be identified and critical concentrations determined and linked with expression of oxidative stress-sensitive transcription factors to help identify mechanisms underlying toxic and carcinogenic effects of iAs.